The goal of this proposal is to provide Dr. Davis with a comprehensive 5-year training program which will allow her to emerge as an independent academic endocrinologist. Through this program she will gain valuable research experience in the fields of islet cell biology, in vivo physiology, genetics, cell cycle regulation, bioinformatics, biostatistics and transcriptional regulation. Dr. Alan Attie will serve as the primary mentor for her career and scientific development. Dr. Attie is a recognized leader in the fields of diabetes, genetics, biochemistry, lipidology, and obesity research. He has a proven track record of mentoring successful basic scientists. Dr. Davis has also assembled a mentoring committee comprised of outstanding physician scientists to provide the full spectrum of career development and scientific guidance. Her mentoring committee includes Dr. Marc Drezner, Dr. Molly Carnes, Dr. Jon Odorico, and Dr. Anath Shalev. The research plan involves the study of beta cell proliferation and will utilize multiple models to elucidate the mechanisms that drive this process. Beta cell proliferation is a critical process in the expansion of islet mass in response to insulin resistance and obesity. Decompensation in the form of hyperglycemia occurs when the beta cell mass is inadequate to meet demands. The BTBR mouse becomes severely diabetic when made obese by introduction of the ob leptin mutation. This model of obesity-associated type 2 diabetes has been shown to have a defect in islet cell proliferation. The central hypothesis is that failure to upregulate FoxM1 or survivin, two key cell cycle regulators, leads to decreased proliferation and ultimately hyperglycemia. The specific aims of this proposal include 1) Examine the role of FoxM1 in promoting beta cell proliferation in vitro and in the BTBR-ob model of type 2 diabetes;2) Determine if survivin is sufficient to drive beta cell proliferation in vitro and in the BTBR-ob model of type 2 diabetes. Together, these aims will allow identification of a novel pathway in beta cell proliferation that may serve as a therapeutic target to expand beta cell mass. PUBLIC HEALTH RELEVANCE: Diabetes is a disease that affects at least 1 in 15 Americans and is estimated to cost at least $132 billion annually. This research aims to understand the fundamental mechanisms that underlie the development of this disease in association with obesity with an ultimate goal of uncovering new therapeutic strategies that may help halt or slow progression of this devastating disease.